In the field of obstetrics, one of the most important problems is the management of preterm labor. A significant number of the pregnancies progressing past 20 weeks of gestation experience premature labor and delivery, which is a leading cause of neonatal morbidity and mortality. Despite major advances in neonatal care, retention of the fetus in utero is preferred in most instances.
Tocolytic (uterine-relaxing) agents that are currently in use include .beta.2-adrenergic agonists, magnesium sulfate and ethanol. In addition, oxytocin receptor antagonists are in development. Ritodrine, the leading .beta.2-adrenergic agonist, causes a number of cardiovascular and metabolic side effects in the mother, including tachycardia, increased renin secretion, hyperglycemia (and reactive hypoglycemia in the infant). Other .beta.2-adrenergic agonists, including salbutamol, terbutaline and albuterol have side effects similar to those of ritodrine. Magnesium sulfate at plasma concentrations above the therapeutic range of 4 to 8 mg/dL can cause inhibition of cardiac conduction and neuromuscular transmission, respiratory depression and cardiac arrest, thus making this agent unsuitable when renal function is impaired. Ethanol is as effective as ritodrine in preventing premature labor, but it does not produce a corresponding reduction in the incidence of fetal respiratory distress that administration of ritodrine does.
The present invention may also be used to stop labor preparatory to Cesarean delivery.
The enzyme 5.alpha.-reductase catalyzes the reduction of testosterone (T) to the more potent androgen, 5.alpha.-dihydrotestosterone (dihydrotestosterone" or DHT), as shown below: ##STR1##
5.alpha.-reductase also catalyzes the reduction of progesterone to dihydroprogesterone, as shown below: ##STR2## and the reduction of androstenedione to androstanedione, as shown below: ##STR3##
There are two isozymes of 5.alpha.-reductase in humans. One isozyme (type 1) predominates in the sebaceous glands of facial skin and skin tissue. The other (type 2) predominates in the prostate.
Finasteride (17.beta.-(N-tert-butylcarbamoyl)-3-oxo-4-aza-5.alpha.-androst-1-en-3-one, as shown below, is a potent inhibitor of the human type 2 enzyme. ##STR4## Under the tradename PROSCAR.RTM., finasteride is known to be useful in the treatment of hyperandrogenic conditions, see e.g., U.S. Pat. No. 4,760,071. Finasteride is currently prescribed for the treatment of benign prostatic hyperplasia (BPH), a condition affecting to some degree the majority of men over age 55. Finasteride's usefulness in the treatment of androgenic alopecia and prostatic cancer is described in the following documents: EP 0 285 382, published 5 Oct., 1988, EP 0 285 383, published 5 Oct., 1988 and Canadian patents 1,302,277 and 1,302,276.
Inhibitors of 5.alpha.-reductase type 1 have also been described. See, e.g., U.S. Pat. No. 5,527,807, issued Jun. 18, 1996, WO 93/23420, published Nov. 25, 1993, U.S. Pat. No. 5,510,351, issued Apr. 23, 2013, WO 93/23038, published Nov. 25, 1993, WO 93/23048, published Nov. 25, 1993, WO 93/23041, published Nov. 25, 1993, WO 93/23040, published Nov. 25, 1993, WO 93/23039, published Nov. 25, 1993, U.S. Pat. No. 5,510,485, issued Apr. 23, 1996, WO 94/07861, published Apr. 14, 1994, U.S. Pat. No. 5,359,071, issued Oct. 25, 1994, WO 95/11254, published Apr. 27, 1995, WO 95/00147, published Jan. 5, 1995, WO 95/28928, published Nov. 2, 1995, U.S. Pat. No. 5,516,799, issued May 14, 1996, U.S. Pat. No. 5,278,159, issued Jan. 11, 1994, U.S. Pat. No. 5,324,734, issued Jun. 28, 1994, WO 95/02607, published Jan. 26, 1995, WO 95/32215, published Nov. 30, 1995, WO 96/22100, published Jul. 25, 1996.
Also known are compounds which are potent inhibitors of both 5.alpha.-reductase type 1 and type 2. These include the compounds described in WO 95/12398, published May 11, 1995, WO 95/07926, published Mar. 23, 1995, and WO 95/07927, published Mar. 23, 1995.
RU-486, also known as mifepristone, is known to be a progesterone antagonist. Abdellilah et al., in Progesterone and Mifepristone modify principally the response of circular myometrium to oxytocin in preparturient rats: comparison with response to acetylcholine and to calcium, J. Pharmacol. and Exp. Therp. 265(3):1205-1212 (1993), report that an oral dose of 10 mg/kg of RU-486 on GD 21 was able to induce parturition in pregnant rats treated with 200 mg/kg progesterone subcutaneously.
Mahendroo et al., in 5.alpha.-reduced androgens play a key role in murine parturition, Molecular Endocrinology 10:380-92 (1996) describe a study involving mice homozygous for genetic null mutations of type 1 5.alpha.-reductase. Seventy percent of these mice failed to initiate parturition. In those studies, the serum progesterone levels in the homozygous mutated mice were not markedly different from wild type mice during the later part of pregnancy. Administration of the progesterone antagonist RU-486 was able to induce parturition in 100% of the mice homozygous for genetic null mutations of type 1 5.alpha.-reductase. In addition, administration of 5.alpha.-androstan-3.alpha.,17.beta.-diol (3.alpha.-Adiol) was able to induce parturition in 93% of the homozygous mutated mice.
Benbow and Waddell, in Distribution and Metabolism of Maternal Progesterone in the Uterus, Placenta, and Fetus during Rat Pregnancy, Biology of Reproduction 52:1327-1333 (1995) report that in the rat, plasma progesterone concentration decreases substantially during the last six days of pregnancy.
Flint and Armstrong, in The appearance of an endometrial 20.alpha.-hydroxysteroid dehydrogenase towards the end of pregnancy in the rat, Endocrinology 92:624-627 (1973) describe that in the rat the activity of 5.alpha.-reductase was low at days 14-16 and increased 2.5-fold before the end of pregnancy, and that the activity of 20.alpha.-hydroxy-steroid dehydrogenase increased 3.5-fold during the latter half of gestation. They note that the decrease in peripheral plasma progesterone concentration occurring on day 21 of gestation in the rat has been implicated as a possible cause of the onset of labor.
Howard and Weist, in Progesterone metabolism by uterine tissue of pregnant rats, Steroids 19:35-45 (1972) observed a tenfold increase in metabolic activity of progesterone between day 11 and day 21 of pregnancy when the results were expressed as nanograms of progesterone metabolized per gram of tissue per hour.
Maltier et al. (Parturition in Reproduction in Mammals and Man. Thibault et al (Eds.) Elllipses Publishing, Paris 1993; pp.: 481-501) discuss parturition and note that at the end of pregnancy, the progesterone/oestradiol-17.beta. ratio decreases by 40% in the myometrium.
Marrone and Karavolas, in Progesterone metabolism by the hypothalamus, pituitary, and uterus of the rat during pregnancy, Endocrinology 109:41-45 (1981) report on the in vitro metabolism of progesterone by the hypothalamus, anterior pituitary and uterus of the rat during pregnancy and observed increased metabolism of progesterone by the uterus at the end of pregnancy and decrease of 5.alpha.-reductase activity in the pituitary.
Myatt et al., in Identification and changes in concentration of prostaglandin H synthase isoforms in rat myometrium at parturition Prostaglandins 48:285-296 (1994) note that nuclear progesterone receptor concentrations were maximal on days 16-18 of pregnancy, decreased from days 18 to 22 (delivery) and fell 24 hours postpartum in the rat.